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VDJtargeting SIGNED

Engineering T cells and B cells for Immunotherapy using V(D)J recombination

Total Cost €

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EC-Contrib. €

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Partnership

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 VDJtargeting project word cloud

Explore the words cloud of the VDJtargeting project. It provides you a very rough idea of what is the project "VDJtargeting" about.

rag    ameliorate    adeno    safe    promoterless    autoimmunity    recognition    differentiated    sequences    engineer    cell    diminished    oncogenic    previously    integrate    manipulations    allelic    switching    chains    express    vectors    diseases    rss    constant    immunotherapy    clinical    antibody    reliance    integration    gene    expression    memory    off    proliferation    retention    models    receptor    negative    spurious    reduces    tcr    chimeric    vivo    mice    maturation    autoimmune    affinity    engineered    adverse    ve    risk    flanked    recombination    facilitated    hypermutation    auto    efficient    coding    somatic    disease    injected    promoter    efficacy    expressed    na    subjected    scaling    endogenous    inserted    loci    antigen    potent    car    locus    reducing    cancers    rare    inducibly    expressing    ab    class    cancer    secret    aav    antigenic    utilizing    lymphocytes    accompanied    region    implanted    signal       escape    desired    secreted    shown    ex    cells    lack    mainly    therapeutic    haematological    engineering    genetic    vdj    activating    exclusion    incorporate    immune    iuml    activation    genes    date   

Project "VDJtargeting" data sheet

The following table provides information about the project.

Coordinator
TEL AVIV UNIVERSITY 

Organization address
address: RAMAT AVIV
city: TEL AVIV
postcode: 69978
website: http://www.tau.ac.il/

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Israel [IL]
 Total cost 1˙496˙875 €
 EC max contribution 1˙496˙875 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2017-STG
 Funding Scheme ERC-STG
 Starting year 2017
 Duration (year-month-day) from 2017-10-01   to  2022-09-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    TEL AVIV UNIVERSITY IL (TEL AVIV) coordinator 1˙496˙875.00

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 Project objective

T cell engineering has shown clinical success mainly in haematological cancers, but scaling up is challenging due to reliance on ex vivo manipulations. In addition, B cell engineering has not shown therapeutic efficacy to date. Here, we propose a novel immunotherapy approach, allowing safe and efficient engineering of B cells and T cells, both ex vivo and in vivo. We will use adeno associated vectors (AAV) to integrate chimeric antigen receptor (CAR) or T cell receptor (TCR) genes into loci coding TCR chains and to integrate antibody (Ab) genes into loci coding Ab chains. Previously, we used AAV facilitated gene targeting in vivo to ameliorate genetic diseases in mice. For lymphocytes we develop “VDJ targeting”: A promoterless receptor/Ab gene flanked by recognition signal sequences (RSS) will be inserted into the endogenous locus by the recombination activating gene (RAG) complex during V(D)J recombination. Only developing lymphocytes, expressing RAG, will incorporate the receptor/Ab gene, which will thus be expressed in potent naïve cells from the strong endogenous promoter. Targeted developing cells are subjected to negative selection, thus reducing risk of adverse autoimmunity. Lack of promoter reduces spurious expression and oncogenic risk upon rare off-target integration. Targeting endogenous loci may allow allelic exclusion. In B cells it may allow utilizing the endogenous constant region to express a B cell receptor and, upon activation, a secreted Ab. Activation may be accompanied by proliferation and affinity maturation, including somatic hypermutation and class switching, to allow a potent immune response, memory retention and diminished antigenic escape. Where controlled autoimmunity is desired, we will engineer B cells to inducibly secret an auto-Ab. We will demonstrate efficacy in cancer and autoimmune disease models implanted with lymphocytes that we engineered while ex vivo differentiated and in mice injected with vectors for in vivo VDJ targeting.

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